A common and debilitating side effect of cranial radiation therapy is a permanent and continually progressive decline in cognition that includes impaired learning and memory, Although previous work has implicated altered hippocampal function in this deficit, we show for the first time that cranial radiation injures adult neural stem cells, ablates hippocampal neurogenesis and permanently disrupts the hippocampal microenvironment making it unable to support neurogenesis, even following reconstitution with non-irradiated stem cells, The irradiated hippocampal subgranule zone displays two important long-term alterations that may account for its inability to support neurogenesis: a loss of normal neural stem cell activity and disruption of the "neuro-angiogenic" microenvironment. The proposed experiments further characterize the radiation sensitivity of adult neural stem cells and explore the potential utility of radio-protective as well as reconstitution strategies to reduce the impact of radiation on neurogenesis in the adult brain.